Prognostic Risk Factors in Randomized Clinical Trials of Face-to-Face and Internet-Based Psychotherapy for Depression: A Systematic Review and Meta-Regression Analysis.

Importance: Variables such as severe symptoms, comorbidity, and sociodemographic characteristics (eg, low educational attainment or unemployment) are associated with a poorer prognosis in adults treated for depressive symptoms. The exclusion of patients with a poor prognosis from RCTs is negatively associated with the generalizability of research findings. Objective: To compare the prognostic risk factors (PRFs) in patient samples of RCTs of face-to-face therapy (FTF) and internet-based therapy (IBT) for depression. Data Sources: PsycINFO, Cochrane CENTRAL, and reference lists of published meta-analyses were searched from January 1, 2000, to December 31, 2021. Study Selection: RCTs that compared FTF (individual or group therapy) and IBT (guided or self-guided interventions) against a control (waitlist or treatment as usual) in adults with symptoms of depression were included. Data Extraction and Synthesis: Data were extracted by 2 independent observers. The Cochrane revised risk-of-bias tool was used to assess the risk of bias. The study was preregistered with OSF Registries and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The primary outcome was the standardized mean difference (Hedges g effect size) in depressive symptoms at treatment termination (assessed with standard patient self-report questionnaires), with a positive standardized mean difference indicating larger improvements in the intervention compared with those in the control group. Meta-regression analyses were adjusted for the type of control group. Three preregistered and 2 exploratory sensitivity analyses were conducted. A prognostic risk index (PROG) was created that calculated the sum of 12 predefined individual indicators, with scores ranging from 0 to 12 and higher scores indicating that a sample comprised patients with poorer prognoses. Results: This systematic review and meta-regression analysis identified 105 eligible RCTs that comprised 18 363 patients. In total, 48 studies (46%) examined FTF, and 57 studies (54%) examined IBT. The PROG was significantly higher in the RCTs of FTF than in the RCTs of IBT (FTF: mean [SD], 3.55 [1.75]; median [IQR], 3.5 [2.0-4.5]; IBT: mean [SD], 2.27 [1.66]; median [IQR], 2.0 [1.0-3.5]; z = -3.68, P < .001; Hedges g = 0.75; 95% CI, 0.36-1.15). A random-effects meta-regression analysis found no association of the PROG with the effect size. Sensitivity analyses with outliers excluded and accounting for risk of bias or small-study effects yielded mixed results on the association between the PROG and effect size. Conclusions and Relevance: The findings of this systematic review and meta-regression analysis suggest that samples of RCTs of FTF vs IBT differ with regard to PRFs. These findings have implications for the generalizability of the current evidence on IBT for depression. More RCTs of internet-based interventions with clinically representative samples are needed, and the reporting of PRFs must be improved.

Human contact in internet-based interventions for depression: A pre-registered replication and meta-analysis of randomized trials.

Introduction: Internet-based self-help interventions have shown to be effective in the treatment of depression. Several meta-analyses indicated that human contact has a crucial impact on adherence and outcome. While most research focused on the role of guidance during interventions, a review by Andersson and Johansson (2012) suggested that contact before the intervention too may play an important role. Objective: We investigated the impact of the degree of contact in internet-based interventions (IBIs) for depression on outcome in adults suffering from elevated symptoms of depression. Methods: We conducted a preregistered meta-analysis (www.osf.io/4mzyd) and included trials comparing IBIs for depression against control conditions (treatment as usual [TAU] or waiting list [WL]) in patients with symptoms of unipolar depression searching the databases PsycINFO and Cochrane's Central Register of Controlled Trials (CENTRAL) limited to entries from EMBASE and PubMed. Following Andersson and Johansson (2012), contact before an intervention was defined as having had a diagnostic interview before the IBI, and contact during intervention was defined as having received guidance during the IBI. IBIs were grouped as providing (0) no contact, (1) contact before the IBI, (2) contact during the IBI, or (3) contact both before and during the IBI. The primary outcome was standardized mean difference (SMD) of the IBI and control in depressive symptoms at treatment termination. Secondary outcomes were study dropout and adherence to the IBI. Results: We included 56 eligible trials that randomized 13,335 patients to 75 internet-based intervention conditions and control groups (TAU in 23 trials, WL in 33 trials). In total, 44 trials (78.57 %) were judged to show some concerns or a high risk of bias. Overall heterogeneity was high regarding the primary outcome (I2s < 66 %) and even higher for secondary outcomes (I2s < 91 %). Degree of contact was a robust predictor of outcome and adherence in all pre-registered and exploratory analyses. We found the effect of the IBI to increase with higher degree of contact. However, in pair-wise contrasts, only IBIs offering both contact before and during the intervention (SMD = 0.573, 95 % CI: 0.437, 0.709) significantly outperformed interventions offering no contact (SMD = 0.224, 95 % CI: 0.090, 0.340). Conclusions: The results suggest that contact before and during an intervention increases the effects of IBIs. The combination of contact before and during the intervention seems to a pivotal role regarding adherence as well as treatment outcome for patients suffering from depression.

Lay Perspectives on Empathy in Patient-Physician Communication: An Online Experimental Study.

Research indicates that patients consider empathy as a key factor contributing to the quality-of-care. However, ambiguities in the definition of this multidimensional construct complicate definite conclusions to-date. Addressing the challenges in the literature, and using a hypothetical physician-patient interaction which explored patient-perceived differences between expressions of affective empathy, cognitive empathy, compassion and no empathy, this study aimed to test whether lay participants' evaluations of the quality-of-care depend on the type of empathic physician behavior, and on the physician's gender. We conducted a randomized web-based experiment using a 4 (type of empathy) by 2 (physician gender) between-subjects design. Empathy was subdivided into three concepts: first, affective empathy (i.e. feeling with someone); second, cognitive empathy (i.e. understanding); and third, compassion (i.e. feeling for someone and offering support). Perceived quality-of-care was the primary outcome. Compared with non-empathic interactions, quality-of-care was rated higher when physicians reacted cognitively empathic or compassionate (d = 0.71; 0.43 to 1.00 and d = 0.68; 0.38 to 0.98). No significant difference was found between affective empathy and no empathy (d = 0.13; -0.14 to 0.42). The physician's gender was not related with quality-of-care. Aspects of participants' personality but not their age, gender or the number of physician visits were associated with quality-of-care. No interactions were observed. In showing that patients rated quality-of-care higher when physician reactions were described as cognitively empathic and compassionate, as compared with affectively empathic or non-empathic, our findings refine views about the kinds of empathy that are important in patient care with implications for clinical practice, education and communication trainings.

Strength-based methods - a narrative review and comparative multilevel meta-analysis of positive interventions in clinical settings.

OBJECTIVE: In psychotherapy, strength-based methods (SBM) represent efforts to build on patients' strengths while addressing the deficits and challenges that led them to come to therapy. SBM are incorporated to some extent in all major psychotherapy approaches, but data on their unique contribution to psychotherapy efficacy is scarce. METHODS: First, we conducted a systematic review and narrative synthesis of eight process-outcome psychotherapy studies that investigated in-session SBM and their relation to immediate outcomes. Second, we conducted a systematic review and multilevel comparative meta-analysis contrasting strength-based bona fide psychotherapy vs. other bona fide psychotherapy at post-treatment (57 effect sizes nested in 9 trials). RESULTS: Despite their methodological variability, the pattern of results in the process-outcome studies was generally positive, such that SBM were linked with more favorable immediate, session-level patient outcomes. The comparative meta-analysis found an overall weighted average effect size of g = 0.17 (95% CIs [0.03, 0.31], p < .01) indicating a small but significant effect in favor of strength-based bona fide psychotherapies. There was non-significant heterogeneity among the effect sizes (Q(56) = 69.1, p = .11; I2 = 19%, CI [16%, 22%]). CONCLUSION: Our findings suggest that SBMs may not be a trivial by-product of treatment progress and may provide a unique contribution to psychotherapy outcomes. Thus, we recommend integration of SBM to clinical training and practice across treatment models.

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions.

OBJECTIVES: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. STUDY DESIGN AND SETTING: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty four items were identified and grouped as per the template for intervention description and replication (TIDieR) domains. Twenty nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey. A multidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. RESULTS: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider's allegiance, and the adherence of providers and participants. CONCLUSION: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines.

Intensity of Treatment as Usual and Its Impact on the Effects of Face-to-Face and Internet-Based Psychotherapy for Depression: A Preregistered Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Treatment as usual (TAU) is the most frequently used control group in randomized trials of psychotherapy for depression. Concerns have been raised that the heterogeneity of treatments in TAU leads to biased estimates of psychotherapy efficacy and to an unclear difference between TAU and control groups like waiting list (WL). OBJECTIVE: We investigated the impact of control group intensity (i.e., amount and degree to which elements of common depression treatments are provided) on the effects of face-to-face and internet-based psychotherapy for depression. METHODS: We conducted a preregistered meta-analysis (www.osf.io/4mzyd). We included trials comparing psychotherapy with TAU or WL in patients with symptoms of unipolar depression. Six indicators were used to assess control group intensity. PRIMARY OUTCOME: Standardized mean difference (SMD) of psychotherapy and control in depressive symptoms at treatment termination. RESULTS: We included 89 trials randomizing 14,474 patients to 113 psychotherapy conditions and 89 control groups (TAU in 42 trials, WL in 47 trials). Control group intensity predicted trial results in preregistered (one-sided ps < 0.042) and exploratory analyses. Psychotherapy effects were significantly smaller (one-sided p = 0.002) in trials with higher intensity TAU (SMD = 0.324, CI 0.209 to 0.439) than in trials with lower intensity TAU (SMD = 0.628, CI 0.455 to 0.801). Psychotherapy effects against lower intensity TAU did not differ from effects against WL (two-sided p = 0.663). CONCLUSIONS: Our results suggest that variation in TAU intensity impacts the outcome of trials. More scrutiny in the design of control groups for clinical trials is recommended.

The effects of patients' expectations on surgery outcome in total hip and knee arthroplasty: a prognostic factor meta-analysis.

Patients' expectations are among the most frequently studied psychological prognostic factors in total knee and hip arthroplasty (TKA/THA). So far, however, evidence on the effect of patients' preoperative expectations on surgery outcome is inconclusive. Heterogeneity of expectation constructs and the use of psychometrically not evaluated measurement instruments have constituted major obstacles for the integration of the current literature. Using a theory-based model of expectation constructs , this meta-analysis set out to disentangle the conflicting results in the current literature. Systematic literature searches yielded k = 46 studies (N = 10,465) that reported associations of preoperative expectations with postoperative pain, functioning and disability, and satisfaction. Random effects meta-analysis revealed a robust small association (r = .16; 95% CI .13, .19) between patients' positive preoperative expectations and better postoperative outcomes. This effect did not differ between THA and TKA, different outcome categories and different follow-up periods. Studies using psychometrically evaluated expectation measures reported significantly higher effects (r = .19; 95% CI .16, .22). Whether this effect varies among different expectation constructs remains unclear. High-quality studies using validated, multidimensional expectation measures are needed to further understand the role of different expectation constructs in THA and TKA surgery.

[Maintaining a Strong Therapeutic Alliance: Initial Experiences with the Alliance-Focused Training (AFT) in Germany]. / Umgang mit Spannungen und Krisen in der therapeutischen Beziehung: Erste Erfahrungen mit einem handlungsorientierten Ausbildungs- und Supervisionskonzept.

AIMS: Alliance Focused Training (AFT) 1 aims at enhancing therapists' competences in resolving ruptures in the therapeutic alliance using video recordings and role-plays. This pilot study funded by the Heigl Foundation aimed at presenting initial results and clinical experiences with AFT in Germany, and to prepare a subsequent RCT. METHODS: 7 trainee therapists participated. Therapies of 15 patients with depressive disorder were analyzed. RESULTS AND CONCLUSION: Trainees experienced AFT as very helpful for their professional development and for dealing with alliance ruptures. The therapeutic competence significantly improved both in self and in observer ratings. The results indicate that AFT is a promising approach to improve psychotherapy training, emphasizing the relevance of the planned proof of concept RCT.

Facilitative interpersonal skills performance test: Psychometric analysis of a German language version.

OBJECTIVE: This study aimed at a psychometric analysis of the Facilitative Interpersonal Skills (FIS) performance test, a test of therapist relational skills that has repeatedly been found to predict psychotherapy outcome. We investigated the reliability, unidimensionality, and convergent validity of a German language version and psychometrics relevant for repeated and short assessments. METHOD: Thirty-nine trainee therapists took the FIS performance test and responded to self-report scales. RESULTS: Inter-rater agreement and internal consistency were high. The findings suggest that the FIS is a unidimensional scale. Correlations between the FIS and self-reported social skills, interpersonal problems, and working involvement were absent to low. FIS performance was independent from specific video stimuli and there was no indication of temporal effects. CONCLUSIONS: The findings suggest that the FIS is robust and ready to be used in repeated assessments and in short form. Further conceptual clarification of the FIS is needed.

Let's Distinguish Relative and Absolute Efficacy to Move Psychotherapy Research Forward.

Objective: Background regarding a recent debate between Cuijpers et al. (2019a, b) and the authors (Munder et al. 2019) about the efficacy of psychotherapy for depression is given. Method: A main reason for the discrepancy in Cuijpers et al.'s and our conclusions is discussed. Results: In our view the discrepancy is due, among other things, to a blurred distinction between questions of relative and absolute efficacy of psychotherapy. Although the efficacy of psychotherapy vis-à-vis alternative treatments may be ambiguous, there can be little doubt about the benefits of psychotherapy relative to no treatment. Conclusion: We do not think that raising fundamental concerns about the value of psychotherapy is a service to the field. We argue that moving the field forward requires a focus on how psychotherapy works and how the access to psychotherapy can be increased.

Focusing on Patients' Existing Resources and Strengths in Cognitive-Behavioral Therapy and Psychodynamic Therapy: A Systematic Review and Meta-Analysis.

Objectives: Integrating a stronger focus on patients' existing strengths in traditional psychotherapy approaches is suggested by recent developments in psychological science, positive psychology, and psychotherapy research. However, the empirical status of treatments focusing on patients' existing strengths is unclear. The aim of this study was to conduct a systematic review (PROSPERO registration CRD42017054362) of studies on adaptations of traditional treatment approaches (e. g., cognitive-behavior therapy or psychodynamic therapy) explicitly focused on using patients' existing resources and strengths (hereafter, resource-focused treatments; RFT). Methods: Extensive systematic literature search yielded k = 11 treatment comparisons from 10 studies contrasting RFTs with either an alternative psychotherapeutic approach or wait list. Effect sizes controlling for pre-treatment differences (gPPWC) and standard Hedges's g effect sizes (gPOWC) were aggregated with random-effects methods Results: Across 8 direct comparisons, RFTs were superior to other psychotherapeutic approaches, as indicated by small to moderate (gPPWC = -0.349, 95 % CI -0.576, -0.122, p = .003, I2 = 46.50 %) and small effect sizes (gPOWC = -0.190, 95 % CI -0.355, -0.025, p = .024, I2 = 0.00 %) in favor of RFTs. Sensitivity analyses corroborated results. Many included studies were characterized by limited sample size, risk of bias or researcher allegiance. Conclusions: This meta-analysis showed preliminary evidence for the benefits of RFTs and suggests an intensification of further research efforts. The evidence was most convincing for hypnotherapeutic-systemic interventions as an add-on for cognitive-behavioral therapy.

Yeast two-hybrid screening reveals a dual function for the histone acetyltransferase GcnE by controlling glutamine synthesis and development in Aspergillus fumigatus.

The acetyltransferase GcnE is part of the SAGA complex which regulates fungal gene expression through acetylation of chromatin. Target genes of the histone acetyltransferase GcnE include those involved in secondary metabolism and asexual development. Here, we show that the absence of GcnE not only abrogated conidiation, but also strongly impeded vegetative growth of hyphae in the human pathogenic fungus Aspergillus fumigatus. A yeast two-hybrid screen using a Saccharomyces cerevisiae strain whose tRNA molecules were specifically adapted to express A. fumigatus proteins identified two unprecedented proteins that directly interact with GcnE. Glutamine synthetase GlnA as well as a hypothetical protein located on chromosome 8 (GbpA) were identified as binding partners of GcnE and their interaction was confirmed in vivo via bimolecular fluorescence complementation. Phenotypic characterization of gbpA and glnA deletion mutants revealed a role for GbpA during conidiogenesis and confirmed the central role of GlnA in glutamine biosynthesis. The increase of glutamine synthetase activity in the absence of GcnE indicated that GcnE silences GlnA through binding. This finding suggests an expansion of the regulatory role of GcnE in A. fumigatus.

"Gold Standards," Plurality and Monocultures: The Need for Diversity in Psychotherapy.

For psychotherapy of mental disorders, presently several approaches are available, such as interpersonal, humanistic, systemic, psychodynamic or cognitive behavior therapy (CBT). Pointing to the available evidence, proponents of CBT claim that CBT is the gold standard. Some authors even argue for an integrated CBT-based form of psychotherapy as the only form of psychotherapy. CBT undoubtedly has its strengths and CBT researchers have to be credited for developing and testing treatments for many mental disorders. A critical review, however, shows that the available evidence for the theoretical foundations of CBT, assumed mechanisms of change, quality of studies, and efficacy is not as robust as some researchers claim. Most important, there is no consistent evidence that CBT is more efficacious than other evidence-based approaches. These findings do not justify regarding CBT as the gold standard psychotherapy. They even provide less justification for the idea that the future of psychotherapy lies in one integrated CBT-based form of psychotherapy as the only type of psychotherapy. For the different psychotherapeutic approaches a growing body of evidence is available. These approaches have their strengths because of differences in their respective focus on interpersonal relationships, affects, cognitions, systemic perspectives, experiential, or unconscious processes. Different approaches may be suitable to different patients and therapists. As generally assumed, progress in research results from openness to new ideas and learning from diverse perspectives. Thus, different forms of evidence-based psychotherapy are required. Plurality is the future of psychotherapy, not a uniform "one fits all" approach.

Cochrane's risk of bias tool in the context of psychotherapy outcome research.

The Cochrane risk of bias tool (RoB) is a widely used measure for methodological quality of randomized controlled trials. This paper discusses RoB's rationale and risk of bias domains, reports on its application in current psychotherapy meta-analyses, and offers comments regarding the application of RoB in the context of psychotherapy outcome research. Our suggestions include focusing on patient's and therapist's expectations when judging the domain "blinding of personnel and participants" and paying greater attention to the domain "selective outcome reporting" and to matters of "treatment implementation."

Generation of an arginine-tRNA-adapted Saccharomyces cerevisiae strain for effective heterologous protein expression.

The tRNA population reflects the codon bias of the organism and affects the translation of heterologous target mRNA molecules. In this study, Saccharomyces cerevisiae strains with modified levels of rare tRNA were engineered, that allowed efficient generation of recombinant proteins with unfavorable codon usage. We established a novel synthetic tRNA expression cassette and verified functional nonsense suppressor tRNAGlnSCUA generation in a stop codon read-through assay with a modified ß-galactosidase reporter gene. Correlation between altered tRNA and protein level was shown by survival of copper sensitive S. cerevisiae cells in the presence of copper ions by an increased transcription of tRNAArgCCG molecules, recognizing rare codons in a modified CUP1 gene. Genome integration of tRNA expression cassette led to the generation of arginine-tRNA-adapted S. cerevisiae strains, which showed elevated tRNA levels (tRNAArgCCG, tRNAArgGCG and tRNAArgUCG) pairing to rare codons. The modified strain MNY3 revealed a considerably improved monitoring of protein-protein interaction from Aspergillus fumigatus bait and prey sequences in yeast two-hybrid experiments. In future, this principle to overcome limited recombinant protein expression by tRNA adaption of expression strains instead of codon adaption might provide new designer yeast cells for an efficient protein production and for improved genome-wide protein-protein interaction analyses.

Psychodynamic Therapy: As Efficacious as Other Empirically Supported Treatments? A Meta-Analysis Testing Equivalence of Outcomes.

OBJECTIVE: Pharmacotherapy, cognitive-behavioral therapy (CBT), and psychodynamic therapy are most frequently applied to treat mental disorders. However, whether psychodynamic therapy is as efficacious as other empirically supported treatments is not yet clear. Thus, for the first time the equivalence of psychodynamic therapy to treatments established in efficacy was formally tested. The authors controlled for researcher allegiance effects by including representatives of psychodynamic therapy and CBT, the main rival psychotherapeutic treatments (adversarial collaboration). METHOD: The authors applied the formal criteria for testing equivalence, implying a particularly strict test: a priori defining a margin compatible with equivalence (g=0.25), using the two one-sided test procedure, and ensuring the efficacy of the comparator. Independent raters assessed effect sizes, study quality, and allegiance. A systematic literature search used the following criteria: randomized controlled trial of manual-guided psychodynamic therapy in adults, testing psychodynamic therapy against a treatment with efficacy established for the disorder under study, and applying reliable and valid outcome measures. The primary outcome was "target symptoms" (e.g., depressive symptoms in depressive disorders). RESULTS: Twenty-three randomized controlled trials with 2,751 patients were included. The mean study quality was good as demonstrated by reliable rating methods. Statistical analyses showed equivalence of psychodynamic therapy to comparison conditions for target symptoms at posttreatment (g=-0.153, 90% equivalence CI=-0.227 to -0.079) and at follow-up (g=-0.049, 90% equivalence CI=-0.137 to -0.038) because both CIs were included in the equivalence interval (-0.25 to 0.25). CONCLUSIONS: Results suggest equivalence of psychodynamic therapy to treatments established in efficacy. Further research should examine who benefits most from which treatment.

Why do psychotherapists participate in psychotherapy research and why not? Results of the Attitudes to Psychotherapy Research Questionnaire with a sample of experienced German psychotherapists.

OBJECTIVE: Psychotherapy research needs to convince psychotherapists to contribute their time and effort to participate. The present paper describes the development and first results of the Attitudes to Psychotherapy Research Questionnaire (APRQ). METHOD: The APRQ and additional qualitative questions about exclusion criteria for participation were filled out by a sample of 365 therapists (psychoanalytic, psychodynamic, and cognitive-behavioral) during an Internet-based research survey. RESULTS: A principle component analysis yielded six factors: Benefits, Damage, Legitimation, Self-doubt, Effectiveness Doubt and External Reasons. Age, external reasons and benefits predicted willingness to participate independent of therapeutic school. DISCUSSION: Results show a changing trend to more positive attitudes to psychotherapy research. To be willing to participate in future research, therapists expected high quality designs, financial compensation, and personal gains.

Pretreatment and process predictors of nonresponse at different stages of inpatient psychotherapy.

OBJECTIVE: Up to 50% of psychotherapeutic treatments end without significant improvements. While there is first evidence about predictors of nonresponse in outpatient psychotherapy, there are currently no studies investigating predictors of nonresponse in inpatient settings. Based upon a previous systematic literature review, we analyzed the predictive value of initial patient characteristics on nonresponse in symptom distress. METHODS: Treatment episodes from 546 patients, treated for at least 4 weeks, were assessed under naturalistic conditions. Nonresponse status (i.e., lack of a reliable improvement in symptom distress) was investigated at four different time points: at week 4, at discharge, and at a two follow-ups (3 and 12 months after discharge). Hierarchical binary logistic regression models were used to predict nonresponse. Sociodemographic data, clinical variables, and the previous response status were entered subsequently in the model. RESULTS: A moderate or functional level of initial symptom distress, a comorbid personality disorder, and previous nonresponse were the most consistent predictors of nonresponse. CONCLUSIONS: The results point to the importance of early outcome assessment and suggest the implementation of more symptom-specific treatments.